Pronunciation:

(a MEE oh da rone)

U.S. Brand Names:

Synonyms:

Generic Available:

Canadian Brand Names:

Use:

Oral: Management of life-threatening recurrent ventricular fibrillation (VF) or hemodynamically unstable ventricular tachycardia (VT)

I.V.: Initiation of treatment and prophylaxis of frequency recurring VF and unstable VT in patients refractory to other therapy. Also, used for patients when oral amiodarone is indicated, but who are unable to take oral medication.

Use - Unlabeled/Investigational:

Conversion of atrial fibrillation to normal sinus rhythm; maintenance of normal sinus rhythm

Prevention of postoperative atrial fibrillation during cardiothoracic surgery

Paroxysmal supraventricular tachycardia (SVT)

Control of rapid ventricular rate due to accessory pathway conduction in pre-excited atrial arrhythmias [ACLS guidelines]

After defibrillation and epinephrine in cardiac arrest with persistent ventricular tachycardia (VT) or ventricular fibrillation (VF) [ACLS guidelines]

Control of hemodynamically stable VT, polymorphic VT or wide-complex tachycardia of uncertain origin [ACLS guidelines]

Pregnancy Risk Factor:

Pregnancy Implications:

Lactation:

Contraindications:

Warnings/Precautions:

Pre-existing pulmonary disease does not increase risk of developing pulmonary toxicity, but if pulmonary toxicity develops then the prognosis is worse. Due to complex pharmacokinetics, it is difficult to predict when an arrhythmia or interaction with a subsequent treatment will occur following discontinuation of amiodarone. May cause optic neuropathy and/or optic neuritis, usually resulting in visual impairment. Corneal microdeposits occur in a majority of patients, and may cause visual disturbances in some patients (blurred vision, halos); these are not generally considered a reason to discontinue treatment.

Caution in surgical patients; may enhance hemodynamic effect of anesthetics; associated with increased risk of adult respiratory distress syndrome (ARDS) postoperatively. Injection contains benzyl alcohol, which has been associated with "gasping syndrome" in neonates. Safety and efficacy of amiodarone in children has not been fully established.

Adverse Reactions:

>10%:

Cardiovascular: Hypotension (I.V. 16%, refractory in rare cases)

Central nervous system (3% to 40%): Abnormal gait/ataxia, dizziness, fatigue, headache, malaise, impaired memory, involuntary movement, insomnia, poor coordination, peripheral neuropathy, sleep disturbances, tremor

Dermatologic: Photosensitivity (10% to 75%)

Endocrine & Metabolic: Hypothyroidism (1% to 22%)

Gastrointestinal: Nausea, vomiting, anorexia and constipation (10% to 33%), AST or ALT level >2X normal (15% to 50%)

1% to 10%:

Cardiovascular: CHF (3%), bradycardia (3% to 5%), AV block (5%), conduction abnormalities, SA node dysfunction (1% to 3%), cardiac arrhythmia, flushing, edema. Additional effects associated with I.V. administration include asystole, cardiac arrest, electromechanical dissociation, ventricular tachycardia, and cardiogenic shock.

Dermatologic: Slate blue skin discoloration (<10%)

Endocrine & metabolic: Hyperthyroidism (<3%), libido decreased

Gastrointestinal: Abdominal pain, abnormal salivation, abnormal taste (oral)

Hematologic: Coagulation abnormalities

Hepatic: Hepatitis and cirrhosis (<3%)

Local: Phlebitis (I.V., with concentrations >3 mg/mL)

Ocular: Visual disturbances (2% to 9%), corneal microdeposits (occur in a majority of patients and lead to visual disturbance in ~10%), halo vision (<5% occurring especially at night), optic neuritis (1%)

Respiratory: Pulmonary toxicity has been estimated to occur at a frequency between 2% and 7% of patients (some reports indicate a frequency as high as 17%). Toxicity may present as hypersensitivity pneumonitis; pulmonary fibrosis (cough, fever, malaise); pulmonary inflammation; interstitial pneumonitis; or alveolar pneumonitis. ARDS has been reported in up to 2% of patients receiving I. V. amiodarone, and postoperatively in patients receiving oral amiodarone.

Miscellaneous: Abnormal smell (oral)

<1% (Limited to important or life-threatening): Abnormal renal function, alopecia, cholestasis, delirium, diarrhea, dyskinesias, erectile dysfunction, encephalopathy, hyperglycemia, hypertriglyceridemia, hypotension (oral), impotence, jaw tremor, myoclonic jerks, optic neuropathy, parkinsonian symptoms, photophobia, proarrhythmia, pulmonary edema, QT interval increased, rash, spontaneous ecchymosis, Stevens-Johnson syndrome, ventricular fibrillation

Postmarketing and/or case reports: Acute intracranial hypertension (I.V.), anaphylactic shock, angioedema, aplastic anemia, bone marrow granuloma, bronchiolitis obliterans organizing pneumonia (BOOP), bronchospasm, confusion, disorientation, dyspnea, erythema multiforme, exfoliative dermatitis, gynecomastia, hallucination, hemolytic anemia, hemoptysis, hypoxia, injection site reactions, leukocytoclastic vasculitis, muscle weakness, myopathy, neutropenia, noninfectious epididymitis, pancreatitis, pancytopenia, pleuritis, pruritus, pseudotumor cerebri, SIADH, sinus arrest, thrombocytopenia, toxic epidermal necrolysis, vasculitis, wheezing

Overdosage/Toxicology:

Drug Interactions:

Note: Due to the long half-life of amiodarone, drug interactions may take 1 or more weeks to develop.

Anesthetics (halogenated, inhaled): Amiodarone enhances the myocardial depressant and conduction defects of inhalation anesthetics; monitor.

Azole antifungals: May prolong QTc, potentially leading to malignant arrhythmias; use caution.

Beta-blockers may cause excessive AV block; monitor response.

Calcium channel blockers (diltiazem, verapamil): May cause excessive AV block; monitor.

Cimetidine may increase amiodarone blood levels.

Cholestyramine may decrease amiodarone blood levels.

Cisapride and amiodarone may increase risk of malignant arrhythmias; concurrent use is contraindicated.

Codeine: Analgesic efficacy may be reduced.

Clonazepam effects may be increased by amiodarone.

Cyclosporine: Serum levels may be increased by amiodarone; monitor.

CYP1A2 substrates: Amiodarone may increase the levels/effects of CYP1A2 substrates. Example substrates include aminophylline, fluvoxamine, mexiletine, mirtazapine, ropinirole, theophylline, and trifluoperazine.

CYP2A6 substrates: Amiodarone may increase the levels/effects of CYP2A6 substrates. Example substrates include dexmedetomidine and ifosfamide.

CYP2C8/9 inducers: May decrease the levels/effects of amiodarone. Example inducers include carbamazepine, phenobarbital, phenytoin, rifampin, rifapentine, and secobarbital.

CYP2C8/9 inhibitors: May increase the levels/effects of amiodarone. Example inhibitors include delavirdine, fluconazole, gemfibrozil, ketoconazole, nicardipine, NSAIDs, pioglitazone, and sulfonamides.

CYP2C8/9 substrates: Amiodarone may increase the levels/effects of CYP2C8/9 substrates. Example substrates include fluoxetine, glimepiride, glipizide, nateglinide, phenytoin, pioglitazone, rosiglitazone, sertraline, and warfarin.

CYP2D6 substrates: Amiodarone may increase the levels/effects of CYP2D6 substrates. Example substrates include amphetamines, selected beta-blockers, dextromethorphan, fluoxetine, lidocaine, mirtazapine, nefazodone, paroxetine, risperidone, ritonavir, thioridazine, tricyclic antidepressants, and venlafaxine.

CYP2D6 prodrug substrates: Amiodarone may decrease the levels/effects of CYP2D6 prodrug substrates. Example prodrug substrates include codeine, hydrocodone, oxycodone, and tramadol.

CYP3A4 inducers: CYP3A4 inducers may decrease the levels/effects of amiodarone. Example inducers include aminoglutethimide, carbamazepine, nafcillin, nevirapine, phenobarbital, phenytoin, and rifamycins.

CYP3A4 inhibitors: May increase the levels/effects of amiodarone. Example inhibitors include azole antifungals, ciprofloxacin, clarithromycin, diclofenac, doxycycline, erythromycin, imatinib, isoniazid, nefazodone, nicardipine, propofol, protease inhibitors, quinidine, and verapamil.

CYP3A4 substrates: Amiodarone may increase the levels/effects of CYP3A4 substrates. Example substrates include benzodiazepines, calcium channel blockers, ergot derivatives, mirtazapine, nateglinide, nefazodone, tacrolimus, and venlafaxine.

Digoxin levels may be increased by amiodarone; consider reducing digoxin dose by 50% and monitor digoxin blood levels closely.

Fentanyl: Concurrent use may lead to bradycardia, sinus arrest, and hypotension.

Flecainide blood levels may be increased; consider reducing flecainide dose by 25% to 33% with concurrent use.

Fluoroquinolones (sparfloxacin, gatifloxacin, moxifloxacin): May result in additional prolongation of the QT interval; concurrent use of sparfloxacin is contraindicated.

HMG-CoA reductase inhibitors (lovastatin, simvastatin, and others dependent on CYP3A4 metabolism): Amiodarone inhibits metabolism of lovastatin and/or simvastatin and may increase lovastatin-induced myopathy and rhabdomyolysis. Concurrent use of lovastatin is not recommended, but if unavoidable, dose of lovastatin should not exceed 40 mg/day.

Lidocaine: Amiodarone may increase serum levels/toxicity of lidocaine. Sinus bradycardia may occur with concurrent use.

Macrolide antibiotics: May prolong QTc, potentially leading to malignant arrhythmias. Use caution and evaluate risk:benefit.

Metoprolol blood levels may be increased; monitor response.

Phenytoin blood levels may be increased by amiodarone; amiodarone blood levels may be decreased by phenytoin.

Procainamide and NAPA plasma levels may be increased; consider reducing procainamide dosage by 25% with concurrent use.

Propranolol blood levels may be increased.

Protease inhibitors (amprenavir, indinavir, ritonavir): May increase amiodarone blood levels and toxicity; concurrent use is contraindicated.

QTc interval prolonging agents (including but may not be limited to amitriptyline, bepridil, disopyramide, erythromycin, haloperidol, imipramine, quinidine, pimozide, procainamide, sotalol, and thioridazine): Effect/toxicity increased; use with caution.

Quinidine blood levels may be increased; monitor quinidine trough concentration.

Rifampin may decrease amiodarone blood levels.

Ropivacaine: Cardiac effects during concomitant therapy may be additive.

Theophylline blood levels may be increased.

Thyroid supplements: Amiodarone may alter thyroid function; monitor closely.

Warfarin: Hypoprothrombinemic response increased. Monitor INR closely when amiodarone is initiated or discontinued. Reduce warfarin's dose by ¹/3 to ¹/2 when amiodarone is started.

Ethanol/Nutrition/Herb Interactions:

Food: Increases the rate and extent of absorption of amiodarone. Grapefruit juice increases bioavailability of oral amiodarone by 50% and decreases the conversion of amiodarone to N-DEA (active metabolite); altered effects are possible; use should be avoided during therapy.

Herb/Nutraceutical: St John's wort may decrease amiodarone levels or enhance photosensitization. Avoid ephedra (may worsen arrhythmia). Avoid dong quai.

Stability:

Compatibility:

Y-site administration: Compatible: Amikacin, bretylium, clarithromycin, clindamycin, dobutamine, dopamine, doxycycline, erythromycin lactobionate, esmolol, gentamicin, insulin (regular), isoproterenol, labetalol, lidocaine, metaraminol, metronidazole, midazolam, morphine, nitroglycerin, norepinephrine, penicillin G potassium, phentolamine, phenylephrine, potassium chloride, procainamide, tobramycin, vancomycin. Incompatible: Aminophylline, cefamandole, heparin, sodium bicarbonate. Variable (consult detailed reference): Cefazolin

Compatibility in syringe: Incompatible: Heparin

Compatibility when admixed: Compatible: Dobutamine, lidocaine, potassium chloride, procainamide, propafenone, verapamil. Incompatible: Floxacillin. Variable (consult detailed reference): Furosemide, quinidine

Mechanism of Action:

Pharmacodynamics/Kinetics:

Onset of action: Oral: 3 days to 3 weeks; I.V.: May be more rapid

Peak effect: 1 week to 5 months

Duration after discontinuing therapy: 7-50 days

Note: Mean onset of effect and duration after discontinuation may be shorter in children than adults

Distribution: Vd: 66 L/kg (range: 18-148 L/kg); crosses placenta; enters breast milk in concentrations higher than maternal plasma concentrations

Protein binding: 96%

Metabolism: Hepatic via CYP2C8 and 3A4, major metabolite active; possible enterohepatic recirculation

Bioavailability: Oral: ~50%

Half-life elimination: Terminal: 40-55 days (range: 26-107 days); shorter in children than adults

Excretion: Feces; urine (<1% as unchanged drug)

Dosage:

Oral:

Children: Arrhythmias (unlabeled use):

Loading dose: 10-20 mg/kg/day in 1-2 doses for 4-14 days or until adequate control of arrhythmia or prominent adverse effects occurs; alternative loading dose in children <1 year: 600-800 mg/1.73 m²/day in 1-2 divided doses/day

Maintenance dose: Dose may be reduced to 5 mg/kg/day for several weeks (or 200-400 mg/1.73 m²/day given once daily); if no recurrence of arrhythmia, dose may be further reduced to 2.5 mg/kg/day; maintenance doses may be given 5-7 days/week

Adults:

Ventricular arrhythmias: 800-1600 mg/day in 1-2 doses for 1-3 weeks, then when adequate arrhythmia control is achieved, decrease to 600-800 mg/day in 1-2 doses for 1 month; maintenance: 400 mg/day. Lower doses are recommended for supraventricular arrhythmias.

Prophylaxis of atrial fibrillation following open heart surgery (unlabeled use): 400 mg twice daily (starting in postop recovery) for up to 7 days. An alternative regimen of amiodarone 600 mg/day for 7 days prior to surgery, followed by 200 mg/day until hospital discharge, has also been shown to decrease the risk of postoperative atrial fibrillation. Note: A variety of regimens have been used in clinical trials.

Recurrent atrial fibrillation (unlabeled use): No standard regimen defined; examples of regimens include: Initial: 10 mg/kg/day for 14 days; followed by 300 mg/day for 4 weeks, followed by maintenance dosage of 100-200 mg/day (see Roy D, 2000). Other regimens have been described and are used clinically (ie, 400 mg 3 times/day for 5-7 days, then 400 mg/day for 1 month, then 200 mg/day).

I.V.:

Children:

Arrhythmias (unlabeled use, dosing based on limited data): Loading dose: 5 mg/kg over 30 minutes; may repeat up to 3 times if no response. Maintenance dose: 2-20 mg/kg/day (5-15 mcg/kg/minute) by continuous infusion

Note: I.V. administration at low flow rates (potentially associated with use in pediatrics) may result in leaching of plasticizers (DEHP) from intravenous tubing. DEHP may adversely affect male reproductive tract development. Alternative means of dosing and administration (1 mg/kg aliquots) may need to be considered.

Pulseless VF or VT (PALS dosing): 5 mg/kg rapid I.V. bolus or I.O.

Perfusing tachycardias (PALS dosing): Loading dose: 5 mg/kg I.V. over 20-60 minutes or I.O.; may repeat up to maximum dose of 15 mg/kg/day

Adults:

Breakthrough VF or VT: 150 mg supplemental doses in 100 mL D5W over 10 minutes

Pulseless VF or VT: I.V. push: Initial: 300 mg in 20-30 mL NS or D5W; if VF or VT recurs, supplemental dose of 150 mg followed by infusion of 1 mg/minute for 6 hours, then 0.5 mg/minute (maximum daily dose: 2.2 g)

Prophylaxis of atrial fibrillation following open heart surgery (unlabeled use): 1000 mg infused over 24 hours (starting at postop recovery) for 2 days has been shown to reduce the risk of postoperative atrial fibrillation. Note: A variety of regimens have been used in clinical trials.

Stable VT or SVT (unlabeled use): First 24 hours: 1000 mg according to following regimen

Step 1: 150 mg (100 mL) over first 10 minutes (mix 3 mL in 100 mL D5 W)

Step 2: 360 mg (200 mL) over next 6 hours (mix 18 mL in 500 mL D5W): 1 mg/minute

Step 3: 540 mg (300 mL) over next 18 hours: 0.5 mg/minute

Note: After the first 24 hours: 0.5 mg/minute utilizing concentration of 1-6 mg/mL

Note: When switching from I.V. to oral therapy, use the following as a guide:

<1-week I.V. infusion: 800-1600 mg/day

1- to 3-week I.V. infusion: 600-800 mg/day

>3-week I.V. infusion: 400 mg/day

Recommendations for conversion to intravenous amiodarone after oral administration: During long-term amiodarone therapy (ie, 4 months), the mean plasma-elimination half-life of the active metabolite of amiodarone is 61 days. Replacement therapy may not be necessary in such patients if oral therapy is discontinued for a period <2 weeks, since any changes in serum amiodarone concentrations during this period may not be clinically significant.

Elderly: No specific guidelines available. Dose selection should be cautious, at low end of dosage range, and titration should be slower to evaluate response.

Dosing adjustment in hepatic impairment: Probably necessary in substantial hepatic impairment. No specific guidelines available.

Hemodialysis: Not dialyzable (0% to 5%); supplemental dose is not necessary.

Peritoneal dialysis effects: Not dialyzable (0% to 5%); supplemental dose is not necessary.

Administration:

Oral: Administer consistently with regard to meals. Take in divided doses with meals if high daily dose or if GI upset occurs. If GI intolerance occurs with single-dose therapy, use twice daily dosing.

I.V.: Give I.V. therapy using an infusion pump at a concentration of <2 mg/mL. Slow the infusion rate if hypotension develops. Note: I.V. administration at low flow rates (potentially associated with use in pediatrics) may result in leaching of plasticizers (DEHP) from intravenous tubing. DEHP may adversely affect male reproductive tract development. Alternative means of dosing and administration (1 mg/kg aliquots) may need to be considered.

Monitoring Parameters:

Reference Range:

Test Interactions:

Dietary Considerations:

Patient Education:

Oral: May be taken with food to reduce GI disturbance, but be consistent. Always take with food or always take without food. Do not change dosage or discontinue drug without consulting prescriber. Regular blood work, ophthalmic exams, and cardiac assessment will be necessary while taking this medication on a long-term basis. You may experience dizziness, weakness, or insomnia (use caution when driving, climbing stairs, or engaging in tasks requiring alertness until response to drug is known); hypotension (use caution when rising from sitting or lying position); nausea, vomiting, loss of appetite, stomach discomfort, or abnormal taste (small, frequent meals, frequent mouth care, chewing gum, or sucking lozenges may help); photosensitivity (use sunscreen, wear protective clothing and eyewear, and avoid direct sunlight); or decreased libido (reversible). Report persistent dry cough or shortness of breath; chest pain, palpitations, irregular or slow heartbeat; unusual bruising or bleeding; blood in urine, feces (black stool), vomitus; warmth, swelling, pain, in in calves; muscle tremor, weakness, numbness, or changes in gait; skin rash or irritation; or changes in urinary patterns. Pregnancy/breast-feeding precautions: Do not get pregnant while taking this medication; use appropriate contraceptive measures. Do not breast-feed.

Anesthesia and Critical Care Concerns/Other Considerations:

Cardiac Arrest: The ARREST trial was a randomized, placebo-controlled trial evaluating amiodarone's efficacy in patients who had an out-of-hospital cardiac arrest with pulseless ventricular tachycardia or ventricular fibrillation. The primary endpoint was admission to the hospital with a spontaneous perfusing rhythm. Patients were randomized to receive 300 mg of intravenous amiodarone or placebo after being shocked >3 times, intubated, and receiving 1 mg of epinephrine. Ventricular fibrillation was the most common initial arrhythmia (88%). More patients in the amiodarone group were successfully resuscitated (44% amiodarone; 34% placebo; P=0.03) and admitted to the hospital, but mortality was similar in both groups (possibly due to sample size). More recently, the ALIVE trial compared amiodarone to lidocaine in out-of-hospital cardiac arrest victims whose ventricular fibrillation was resistant to 3 defibrillation attempts in addition to epinephrine and a fourth defibrillation attempt (Dorian, 2002). This was a randomized, double-blind comparison. Other inclusion criteria included ventricular fibrillation unrelated to trauma (or with other arrhythmias that converted to ventricular fibrillation) and recurrent ventricular fibrillation after successful initial defibrillation. The primary endpoint was the number of patients who were admitted to the hospital intensive care unit alive. Three hundred and forty-seven patients were enrolled. The initial amiodarone dose was 5 mg/kg and the lidocaine dose was 1.5 mg/kg. If ventricular fibrillation persisted after another shock, then the study drug could be administered again (amiodarone 2.5 mg/kg, lidocaine 1.5 mg/kg). Significantly more amiodarone patients (~23%) were admitted to the hospital alive than lidocaine patients (12%). The majority (>90%) of patients in the ALIVE trial had ventricular fibrillation as the initial arrhythmia. The authors concluded that intravenous amiodarone is superior to lidocaine in the treatment of shock-resistant, out-of-hospital ventricular fibrillation.

Adverse Events: Although adverse events are less common with 200 mg/day, amiodarone-induced pulmonary toxicity can occur and the patient must be monitored. Patients may present with very mild, nonspecific signs such as dyspnea on exertion or cough.

Cardiovascular Considerations:

Dental Health: Effects on Dental Treatment:

Dental Health: Vasoconstrictor/Local Anesthetic Precautions:

Mental Health: Effects on Mental Status:

Mental Health: Effects on Psychiatric Treatment:

Dosage Forms:

Injection, solution, as hydrochloride: 50 mg/mL (3 mL, 18 mL) [contains benzyl alcohol and polysorbate (Tween®) 80]

Cordarone®: 50 mg/mL (30 mL) [contains benzyl alcohol and polysorbate (Tween®) 80]

Tablet, as hydrochloride [scored]: 200 mg

Cordarone®: 200 mg

Pacerone®: 100 mg [not scored], 200 mg, 400 mg

Extemporaneously Prepared:

Nahata MC and Hipple TF, Pediatric Drug Formulations, 2nd ed, Cincinnati, OH: Harvey Whitney Books Co, 1992.

International Brand Names: